Gastroesophageal Reflux Disease (GERD) is the most common malady of the esophagus and affects over 20% of the US population. While mucosal injury in GERD responds adequately to medical therapy, remedying the GERD symptoms such as heartburn and sensation/awareness of the refluxate movement within the esophagus referred to as regurgitation movement especially in the absence of mucosal injury, which comprises nearly half of this patient population, poses a significant clinical challenge. Thi is primarily due to lack of clear understanding of the cerebral cortical mechanisms involved in sensory physiology and pathophysiology of GERD. The current proposal addresses this deficiency at two levels. At the cerebral cortical level in humans it utilizes advance imaging technology to characterize the effect of chronic and acute esophageal acid exposure on local and large scale cortical networks that are involved in visceral sensation, interoception/homeostasis and awareness in healthy individuals and patients with well defined various GERD sub-types including erosive and non erosive reflux disease as well as functional heartburn. The proposed animal studies will delineate the underlying cortical mechanisms of sensory pathophysiology in GERD using an integrated imaging, molecular, and electrophysiological approach. We have focused these studies on two animal models; repeated acid exposure and chronic erosive esophagitis. These resemble non-erosive and erosive reflux in humans. These investigations complement the human studies and will provide in depth insight into the effect of chronic and acute esophageal acid exposure on the cortex, insight that cannot be obtained from humans. The obtained information will increase our understanding of the cortical sensory pathophysiology of GERD and as such has the potential to lead to newer diagnostic and therapeutic modalities and positively impact clinical practice and potentially reduce health care expenditure. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page